COVID‐19, obesity, and immune response 2 years after the pandemic: A timeline of scientific advances

Summary In the 2 years since the COVID‐19 pandemic was officially declared, science has made considerable strides in understanding the disease's pathophysiology, pharmacological treatments, immune response, and vaccination, but there is still much room for further advances, especially in comprehending its relationship with obesity. Science has not yet described the mechanisms that explain how obesity is directly associated with a poor prognosis. This paper gathers all published studies over the past 2 years that have described immune response, obesity, and COVID‐19, a historical and chronological record for researchers and the general public alike. In summary, these studies describe how the cytokine/adipokine levels and inflammatory markers, such as the C‐reactive protein, are associated with a higher body mass index in COVID‐19‐positive patients, suggesting that the inflammatory background and immune dysregulation in individuals with obesity may be expressed in the results and that adiposity may influence the immune response. The timeline presented here is a compilation of the results of 2 years of scientific inquiry, describing how the science has progressed, the principal findings, and the challenges ahead regarding SARS‐CoV‐2, COVID‐19, and emerging variants, especially in patients with obesity.

rates. [2][3][4] On December 31, 2019, the World Health Organization (WHO) noticed cases of viral "pneumonia of unknown origin" in the Chinese region of Wuhan. Shortly thereafter, the etiologic agent was found to be a coronavirus and its genome was sequenced. The disease name COVID-19 was coined on February 11, 2020, and on March 11, the WHO declared COVID-19 a pandemic due to the sharp rise in the number of cases and deaths worldwide. 5,6 To date, COVID-19 has caused more than 400 million cases and over 6 million deaths, currently ranking as the seventh most lethal virus in human history. 7 A global effort has been put forward to answer questions raised by the disease, including its origin, the impact on human and environmental health, and the best practices for treatment and prevention. As a result, exactly 2 years from the date of the first WHO report, a search using COVID-19 as a keyword in PubMed retrieves 213,121 articles.
However, the immune response against COVID- 19 is not yet fully understood. Questions continue to puzzle immunologists, such as why some individuals are asymptomatic while others who seem to be otherwise healthy may have a severe case of the disease, how long immune memory can last after infection or vaccination, and how the immune system responds to the variants. Nevertheless, it is known that the immune system is involved in confronting the virus itself and the tissue damage that may occur. Briefly, the innate immune system's pathogen-recognition receptors recognize RNA from the virus and trigger the inflammatory production of cytokines, such as interleukin 6 (IL-6), tumour necrosis factor alpha, IL-1, and type I and III interferons in particular. The adaptive immune response is involved when B and T lymphocytes are primed by viral antigens that bind to the Bcell receptor and the T-cell receptor, respectively. T cells can either help the development of the immune response and tissue repair by producing cytokines (CD4 + T cells) or by killing infected cells in an attempt to reduce the viral burden (CD8 + T cells), while B cells produce antibodies that endeavor to neutralize the infective potential of the virus. 8,9 The adaptive immune response is dampened after removing the threat, but T and B memory cells specific to the antigen are generated. As the evidence shows, immunological memory can last for several months with humoralassessed by anti-spike (S), antinucleocapsid (N), and neutralizing antibodiesand cellular componentsparticularly memory B and T cellsexhibiting different kinetics in the peripheral blood. 10,11 Moreover, some form of memory may last years after infection, as suggested by data on antibodies in the context of SARS-CoV infection. 12 Nevertheless, reinfection may occur. While there is still no consensus in the literature as to the criterion used to define reinfection, some studies have shown that it is arguably rare, although emerging variants are likely to play an important role in this phenomenon, as reinfections are usually arise from strains from those of the first infection. [13][14][15][16] Importantly, vaccines seem to activate several pathways in the immune system, including the production of neutralizing and non-neutralizing antibodies, induction of memory T and B cells, enhanced phagocytosis, and induction of type I and III interferons. 17 An important feature of COVID-19 is its higher rate of morbidity and mortality among individuals with comorbidities. 18 Some systematic reviews and meta-analyses have observed that patients with obesity have a higher risk of being hospitalized with a more severe case of the disease and dying. [19][20][21] In addition to its elevated adipose tissue mass, obesity is characterized by low-grade inflammation, or metaflammation, that affects the whole organism. 22 In this context, there is an imbalance in the production of proinflammatory and anti-inflammatory molecules. The adipose tissue also alters the release of its adipokines, which further contributes to the immune imbalance in obesity and changes the energy metabolism circuitry. 22,23 When combined with the metabolic burden imposed by obesity, along with a higher prevalence of pulmonary diseases, immune imbalance may be of prime importance to understanding why patients with obesity are especially vulnerable to COVID-19.
The evidence of immune imbalance in severe COVID-19 patients indicates a compromise in both the innate and adaptive immune systems. 24 Obesity is also significantly associated with  complications, yet it is not well known how the immune system is affected by the double burden of obesity and COVID-19 and whether vaccine protection is less effective in individuals with obesity. This scoping review aimed to answer the following question: What immunological advances have been made in the context of obesity as a comorbidity of COVID-19 2 years after the first report by the WHO?
with their title and/or abstracts referencing at least one word from each of the three groups. The criteria for exclusion were reviews; letters to the editor; editorials; comments; articles that did not add new results to the research question; articles that did not explicitly refer to one or more groups of the search strategy in the title or abstract; articles in which obesity, bodyweight, or BMI was only a comorbidity occurring in a percentage of the patients and was not further correlated or analyzed as an immune aspect of COVID-19; articles without an abstract; and articles from preprint servers. The results were then systematized following the immune system topics and synthesized accordingly.

| RESULTS
A total of 525,735 articles referring COVID-19 were published in the PubMed, Web of Science, and Embase databases. The search combining the three groups of keywords returned 1771 references: 596 from PubMed, 708 from Web of Science, and 467 from Embase. After filtering for duplicates from different databases, 917 references were further screened for eligibility. Out of these, 152 full texts were reviewed after excluding unrelated reviews, letters to the editor and comments (n = 556), articles that did not refer to one or more groups of keywords in their titles or abstracts (n = 127), articles in which obesity was described only as a comorbidity (n = 93), articles without an abstract (n = 4), and articles from preprint servers (n = 27). Eighty-six articles were discarded because they failed to interrelate groups 1, 2, and 3 of the keywords. Finally, a total of 65 articles were included in this scoping review ( Figure 1). During this period, two articles were published using an experimental model with obesity, four articles involving children, and 31 articles involving adults. Most of them evaluated hospitalized patients, many of whom were admitted to an intensive care unit, dead on arrival, or survivors without information on sex or race.

| Obesity, COVID-19, and immune cells
A number of studies have reported that the hematological parameters in hospitalized COVID-19 patients presented higher neutrophil counts, as well lower lymphocyte and eosinophil counts. [25][26][27][28][29][30][31][32][33][34] Cell count of the innate immunity was altered in infected patients with a higher BMI in several studies. 29,[33][34][35][36] The frequency of dendritic cells and monocytes was negatively correlated with BMI in aged COVID-19 patients, 36 while natural killer (NK) cells decreased with BMI in young COVID-19 patients. 36 In general, the neutrophil-to-lymphocyte ratio (NLR) is positively associated with adiposity and severity in COVID-19-positive patients. 25,30,31 In contrast, the lymphocyte count significantly dropped in patients with obesity as compared to those without obesity, and this percentage was significantly associated with death in patients with obesity in univariate and multivariate analyses. 34,37 In addition, sedentary and children with obesity had a lower frequency of T regulatory cells associated with a higher frequency of Th1 cells. 38 The frequency of CD4 + cells in the subgroup of COVID-19 patients with obesity was significantly decreased in the severe group as compared to the non-severe group. 33 Moreover, the percentage of CD19 + cells was higher in overweight and patients with obesity as compared to normal-weight patients. 33 It was observed that the lymphocyte-to-C-reactive protein (CRP) ratio (LCR) and the lymphocyte-to-platelet ratio (LPR) is lower as well. 25 The lymphocyte and platelet counts are negatively correlated with BMI. 34,39 The phenotypic profile of innate and adaptative cells is summarized in Table 2 and Figures 2 and 3.

| Obesity, COVID-19, and immunological molecules
The proinflammatory cytokines and chemokines, such as IL-6, IL-8, tumour necrosis factor (TNF), IL-17, IL-12, IL-1, IP-10, MCP-1, and More women had NLR higher than 6. NLR higher than 6 was significantly associated with Intensive Care Unit (ICU) admission in both men and women, while a ratio higher than 6 was associated with invasive mechanical ventilation and death in women but not in men. 31 100 patients (mean age 55.5 years, 68% male) with COVID-19.
NLR was positively correlated with epicardial adipose volume but was not correlated with epicardial adipose density.
Leukocytes 244 patients diagnosed with COVID-19 and cardiovascular disease (hypertension, coronary heart disease, or heart failure). The patients were categorized into critical (n = 36) and non-critical (n = 208) groups according to China's National Health Commission. Critically ill patients had higher BMI than non-critical patients at admission.
Neutrophil and monocyte counts were higher in critically ill patients at admission. Critically ill patients had lower lymphocyte count at admission than non-critical patients. 29 22 adult (median age: 58.5 years) COVID-19 positive patients admitted to the ICU. The patients were divided into lean (n = 10) and patients with obesity (n = 12) using the percentage of fat mass and age.
There were no differences between the groups in the neutrophil count in blood at the baseline. Comparing the count at the baseline and 10 days after admission, there were no changes in the neutrophil between the groups (baseline vs 10 days). There were no differences between the groups in the lymphocyte count at the baseline. Comparing the count at the baseline and 10 days after admission, there was an increase in the count at day 10 in the lean group only. 26 13 deceased young (14-40 years of age) and 40 young age-and sex-matched survivors from COVID-19. The patients with prolonged shedding had a higher BMI and a higher proportion of patients with obesity. Levels of NK cells on admission were higher in prolonged as compared to non-prolonged shedders.
Among the factors associated with prolonged shedding in a multivariable logistic regression, BMI and NK cells were associated with higher odds ratio, while CD4+ cells were associated with a lower odds ratio of prolonged shedding. CD19+ cell count and percentage were increased in overweight and patients with obesity as compared to normal-weight patients. CD3+ cell percentage was decreased in the blood of patients with obesity as compared to normal weight. Among the patients with obesity, CD4+ cell count was lower in severe patients as compared to non-severe patients.

33
600 patients with COVID-19. The mean BMI of the cohort was 31.5 kg/m 2 , and 301 (50.2%) were classified as patients with obesity. Women comprised 45.4% (273) and had a higher percentage of obesity than men.
In multivariate analysis, absolute lymphocyte count and percentage of lymphocytes were positively associated with BMI after adjustment for age, sex, and race. Lower lymphocyte percent and higher ferritin and D-dimer levels were significantly associated with ICU admission.

43
A 9-year-old boy with obesity presenting fever, loss of appetite, and fatigability at admission. His mother had COVID-19 one month before admission but the patient did not present any symptoms at the time. The case was treated as pediatric inflammatory multisystem syndrome (PIMS) associated with COVID-19.
The patient was treated with intravenous immunoglobulin in a dose of 0.5 g/kg/day for 5 days and methylprednisolone 2 mg/kg/day for 7 days.
The patient presented lymphopenia at the onset (1420/μL) but normalized levels at discharge (7 days later).

44
C57BL/6 mice fed a normal diet or a high-fat diet from 8 weeks of age to 12 weeks of age or 48 weeks of age.
At 48 weeks of age, the high-fat diet-fed mice had lower Ace2 mRNA expression in their intestinal macrophages as compared to 45

| Obesity, COVID-19, and vaccines
High vaccine effectiveness rates for the total population were reported, with slightly lower rates for the elderly and those suffering from hypertension, diabetes, or obesity, although BNT162b2 and mRNA-1273 were reported to have a high efficacy (>89%) in the population with obesity. 87,88 While vaccination does not eliminate the risk of hospitalization or death, the risks are significantly reduced, 89 and this result did not differ between the patients with obesity and the general population in one study. 87 After vaccination, the studies either showed no differences in antibody levels across BMI categories or slightly reduced antibody levels in patients with obesity. [89][90][91][92][93][94] Furthermore, the vaccines were expected to perform well in terms of side effects in the population with obesity, although some minor side effects had different occurrence rates depending on the BMI. 95,96 The vaccine efficacy, antibody response, and side effects after vaccination are summarized in Table 4.

| DISCUSSION
The present scoping review analyzed the studies and their results comprising the association between COVID-19, adiposity, and the branches of the immune system with a focus on answering the primary research question. Overall, adiposity was found to be related to

| Immune cells
Considering the findings on immune cells, the NLR was higher in women, who had higher BMI than men, and was related to the epicardial adipose tissue volume. 25,31 However, based solely on the studies included in the present review, it is not possible to conclude that adiposity is directly associated with the NLR, as one of the included studies failed to observe any association between NLR and BMI, and another only pointed to an indirect relationship mediated by the length of hospital stay. 30,34 A relevant insight, however, may come from the studies analyzing neutrophil and lymphocyte counts.
While neutrophils seem to be positively related to BMI levels, 26,29,33,34 lymphocytes are often lowered in patients with obesity. 26,28,29,32,35,37,39,43 Importantly, the adiposity profile and specific adipose tissue depots, such as the epicardial adipose tissue, may be more accurately related to NLR, as they discriminate adiposity better than the BMI. 25 Indeed, it was observed that the NLR was associated with adiposity markers, particularly waist-to-height ratio and waist-to-hip ratio, although no difference was noted between patients with obesity and individuals without obesity. 97 Moreover, the NLR is Observed characteristic Sample Main findings Reference intestinal macrophages of normal diet-fed mice.
10 patients whose death was due to COVID-19 infection (COVID-19 group) from March to September 2020; 10 patients who had a premortem diagnosis of hypertension, type 2 diabetes mellitus, and chronic kidney disease and had died and had an autopsy performed during the same period (Control group); 5 patients with myocarditis whose autopsy occurred from 2015 to 2020 (Myocarditis group).
In some hearts of the COVID-19 group (the article does not specify the n), there were a significant number of CD68+ cells seen in the epicardial adipose tissue.
LCR negatively correlated with epicardial adipose tissue volume but not with epicardial adipose tissue density.
PLR positively correlated with epicardial adipose tissue volume but not with epicardial adipose tissue density.

25
T A B L E 3 Obesity, COVID-19, and immunological molecules

Observed characteristic Sample Main findings Reference
Cytokines/adipokines A 31-year-old African American female with COVID-19 positive diagnosis, morbid obesity, previous history of childhood asthma, and cutaneous psoriasis presented with 1 week of severe dyspnea on exertion, cough, fever, chills, and myalgia.
Serum IL-6 levels were 4.9 times higher than the upper limit of the reference range (0.0-15.5 pg/ mL).
Leptin levels were increased in the HSF group as compared to the control group and decreased in the HSF + γOz as compared to the HSF group. Adiponectin levels were increased in both HSF and HSF + γOz. Epididymal adipose tissue IL-6, TNF-α, and MCP-1 were increased in the HSF group as compared to the control and HSF + γOz. PPAR-γ expression in the adipose tissue was decreased in the HSF group and recovered in the HSF + γOz group. Authors advocate for the use of γOz as a natural supplement in COVID-19. COVID-19 patients had higher BMI and higher serum leptin than non-COVID-19 patients. Leptin levels correlate with BMI only in COVID-19 patients. The authors propose that leptin is increased due to ACE2-angiotensin II disruption due to the viral infection. In this context, inflammation is exacerbated in the lungs because of higher concentrations of leptin and angiotensin II.

Expression data of SARS-CoV-2-infected and noninfected human epithelial cells (Gene Expression
Omnibus accession number GSE147507).
Using Pathvisio for visualizing the expression of genes of the leptin pathway, it was observed that SOCS3, STAT1, NFKB1, and IL1B were upregulated in infected cells.
TNF-α treated cells do not change their expression of the GRP78 receptor, which this study shows as a molecule capable of binding to the spike protein of SARS-CoV-2 and may concentrate and accumulate the viral particles in ACE-2 expressing cells. 67 13 deceased young (14-40 years old) and 40 young age-and sex-matched survivors.
Deceased patients had higher BMI than survivors and presented higher levels of IL-10 and TNF-α.
IL-6 and IL-4 levels were increased in the serum of patients with obesity, while IL-10 showed no difference between the groups. 28 35 patients with obesity and with metabolic syndrome adult patients were randomly assigned to the placebo (n = 18) and colchicine (n = 17) groups.   BMI correlated positively with CRP levels (r = 0.27, p = 0.05) in the positive group. Positive patients had higher BMI than negative patients.

63
A 9-year-old boy with obesity presenting fever, loss of appetite, and fatigability at admission. His mother had COVID-19 one month before admission but the patient did not present any symptoms at the time. The case was treated as pediatric inflammatory multisystem syndrome (PIMS) associated with COVID-19. The patient was treated with intravenous immunoglobulin in a dose of 0.5 g/kg/day for 5 days and methylprednisolone 2 mg/kg/day for 7 days.
The patient presented high CRP at the onset (>160 mg/L) but normalized levels at discharge (7 days later). total dose of 600 mg was as effective as the 800 mg dose.
Treated rats presented increased expression of the anti-inflammatory receptors angiotensin II receptor type 2 (AT2) and Mas receptor (MasR) and decreased expression of the proinflammatory receptor AT1. Human alveolar type II cells treated with these drugs and the Spyke protein of SARS-CoV-2 presented lower expression of inflammatory cytokines (TNF-α, IL-6, and CCL-2) than untreated cells, exposed to the Spyke protein.

52
Whole blood RNA-seq data from non-infected patients with obesity (n = 20) and without obesity (n = 21) individuals.
NOD2 expression was higher in patients with obesity as compared to individuals without obesity. Obesity and older age lead to higher expression of CD147-related genes on immune cells.

64
Complement 35 patients with obesity and with metabolic syndrome adult patients randomly assigned to the placebo (n = 18) and colchicine (n = 17) groups.
C5a and C9 were decreased in patients receiving colchicine.
Immunohistochemical staining revealed that there was a significant deposition of C5b-9, C3d, and C4d in the endothelium of the subcutaneous adipose tissue (SAT) and vascular damage. Moreover, colocalization of complement proteins and SARS-CoV-2 was observed in the SAT.

65
Lipid mediators 35 adult patients with obesity and metabolic syndrome were randomly assigned to the placebo (n = 18) and colchicine (n = 17) groups.
COX-2 was downregulated in patients with obesity receiving colchicine.  The frequencies of fever <38 C, fever ≥38 C, myalgia, arm soreness, redness, swelling, nausea, red, itchy, swollen or painful rash, headache, loss of appetite, sweating, chills, tiredness, sleepness, and dizziness were all lower in patients with obesity and higher in underweight and normal-weight respondents after the first dose. After the second dose, this association remained for fever <38 C, fever ≥38 C, myalgia, arm soreness, redness, swelling, headache, loss of appetite, sweating, chills, tiredness, sleepness, and dizziness. with CD14 + CXCR6 + cells positively correlated with the elevated BMI and CD68 + cells in the epicardial adipose tissue. 28 The phenotype of monocytes and macrophages is, arguably, of higher relevance than the absolute count since healthy, mild, and severe patients may not differ in the absolute count yet differ in morphological and expression profiles of these cells. [107][108][109] Nevertheless, the difference observed in monocytes may be due to obesity, as a higher cell count was observed in patients with obesity. Moreover, important differences were reported between patients with obesity and individuals without obesity in the classical, non-classical, and intermediate compartments. 110,111 In this regard, the positive correlation between CD14 + CXCR6 + cells and BMI in young infected patients is illustrative, given that CXCR6 is a lung homing marker  Tables 2-4. The date of each result and event is underlined and corresponds to the date of its first appearance in the databases respectively. Although it could not be ascertained whether these findings are directly related to BMI or to the severity of the diseasegiven that few studies have considered patients with obesity -, the literature reports important changes in the blood count and phenotype of these cells in cases involving COVID-19 and obesity. [113][114][115][116] Importantly, these cells are susceptible to the cytokine milieu and The lymphocyte count was the main parameter assessed when considering the adaptive immunity. As mentioned, lymphopenia is a common finding in COVID-19 cases. Following this trend, most studies reported a lower lymphocyte count in patients with obesity as compared to individuals without obesity. Interestingly, non-infected individuals with obesity usually have a higher lymphocyte count than the normal-weight controls. 117,118 However, when it comes to disease severity, obesity is a well-known risk factor. Indeed, severe patients seem to have a different adaptive immune response than patients with milder ones, with a lower lymphocyte count and a delayed and considerably weaker T cell response, which may explain the findings presented here. 9,119 The phenotypic characterization of lymphocytes was also performed in some studies and may be insightful for understanding disease pathogenesis and the immunological nuances of the interaction between obesity and COVID-19. Lower CD4 + T cell count in the blood was associated with disease severity and prolonged viral shedding, whereas lower levels of physical activity and higher BMI were associated with lower frequency of CD4 + Treg cells. 33,38,42 These results corroborate the literature showing circulating CD4 + being affected by the infection and negatively associated with its severity and recovery. 120,121 However, the mechanism for this effect, as well as for the exacerbated lymphopenia in patients with obesity, has not yet been clearly identified but may be the result of the viral attack on these cells, cell death following activation, or redistribution and localization to specific body compartments. 120 The result on Treg cells indicates that the higher BMI and the physical inactivity characteristic of the present pandemic are related to a higher inflammatory background, which could be of great importance for the clinical course of treatment in patients with obesity.
Despite these results, an important feature that was largely overlooked in the studies is the further characterization of the subsets of lymphocytes beyond CD4 + T cells. In general, there is an upregulation of both Th1 and Th17 profiles, including their characteristic cytokines, while Th2 and Treg profiles and their cytokines are downregulated in obesity. [122][123][124][125] The Treg/Th17 ratio is decreased in obesity, and this is related to metabolic health. 126,127 Severe COVID-19, in turn, provokes dampened Th1 and Treg responses, while promoting the Th17 profile. [128][129][130] Similar to obesity, the IL-17/IL-10 ratio is increased in COVID-19 cases, even in deceased patients, as compared to those who improved. 130 The cytokine milieu in these changes plays an important role. As will be discussed in the next section, IL-5 participates in the event of cytokine storm, is often increased in obesity, and skews the polarization to a Th17 profile and away from the Treg profile. 131 Interestingly, TGF-β, a cytokine that along with IL-6 is important for the Th17 development, is more frequently expressed in the leukocytes of children with obesity and has an inverse relationship with IL-10 in neutrophils of children with obesity. 132,133 In this regard, it can be argued that the skewed pattern of CD4 + T cell subsets and their characteristic cytokines, which are already established in obesity, is further deepened in COVID-19, which is a factor for greater severity and a higher mortality rate in patients facing the double burden of obesity and COVID-19.
One study among the articles found in the present review reported a positive correlation between CD4 + central memory T cells and BMI in infected aged patients, while CD8 + cells secreting IFN-γ correlated negatively with BMI in infected young patients. 36 Contrary to total CD4 + cells, which drop sharply in the infection, memory CD4 + cells are effectively formed in COVID-19 patients and readily stimulated in vitro. 134 Like CD4 + cells, the CD8 + cell count is negatively associated with the severity of infection. 121 Thus, the negative correlation found between CD8 + cells secreting IFN-γ and BMI may be reflective of a dampened antiviral response in individuals with obesity. However, it is puzzling that these correlations were observed only in aged or young individuals. Nonetheless, important differences had already been noted in the adaptive immune response when age was considered. 135

| Immune molecules and pathways
The reports on immune molecules focused on the levels of cytokines/ adipokines, CRP, and antibodies, but there were also important reports on immune receptors, complement proteins, lipid mediators, and the enzyme furin. The preference for the study of cytokines/ adipokines and CRP levels may be related to the predictive value of these markers for complications in COVID-19. 119,144 The dysregulated levels of cytokines are of great concern due to the cytokine storm severe patients may face. 145  Among the adipokines, leptin levels were elevated in infected patients, although it may be due to their higher BMI. 62 Lower leptin levels were observed in an animal model supplemented with an antiinflammatory and antioxidant substance, revealing that this molecule may be downregulated by anti-inflammatory agents. 48 Due to its immunometabolic roles, leptin plays a major inflammatory role, triggering inflammatory responses. 152 In fact, one of the studies summarized in the present scoping review revealed that key inflammatory genes in the leptin pathway, SOCS3, STAT1, NFKB1, and IL1B, are upregulated in infected human epithelial cells. 66 Moreover, deceased patients with obesity as one of the comorbidities presented upregulation of genes in the leptin pathway in lung tissue samples. 74 It has been suggested that leptin may be a facilitator of acute pulmonary inflammation, given its immune role and increased angiotensin II, which promotes cardiorespiratory derangements. 62 Taken together, these results point to leptin, in addition to IL-6, as an important inflammatory molecule produced by the adipose tissue that may be responsible for triggering detrimental effects in COVID-19.
There is a trend in the studies denoting higher CRP levels in patients with obesity and a positive association with adiposity. CRP is often higher in patients with obesity as compared to normal-weight controls and is associated with the low-grade inflammation characteristic of obesity. 111,132,153 Blood CRP concentration in COVID-19 cases is a common biomarker for adverse outcomes. 154 As discussed above, IL-6 is a key player in COVID-19 pathogenesis and is often elevated in infected patients with obesity as compared to those without obesity. This cytokine is a potent transcriptional stimulator of CRP in the liver. 155 Therefore, in the case of an infected patient with obesity, there may be a summation of both conditions for elevated CRP levels.
The reviewed studies reveal that obesity is positively associated with the expression of proinflammatory receptors and pathways, and this may be important in COVID- 19. In an animal model of metabolic syndrome, a higher expression of AT1 and MasR receptors was observed, which mediate anti-inflammatory and cardioprotective actions, and the lower expression of the proinflammatory receptor AT2 after the administration of candersatan and captopril. 52 These results suggest that metabolically unhealthy individuals, including those with obesity, may suffer the cardiorespiratory and inflammatory consequences of the dysregulation of the renin-angiotensin system.

| Perspectives
Knowledge of COVID-19 has advanced in various areas since the WHO declared it a pandemic, including those related to the pathogenesis of the disease and the immunopathology that accompanies it. This growing body of information has been crucial to confronting the pandemic, vaccines arguably being the pinnacle of applied knowledge associated with immunity against the virus. It has also extended to diseases that are important risk factors for COVID-19 infection and severity, such as obesity.
Although important results have shed light on the relationship between obesity, COVID-19, and the immune system, there are major gaps that still need to be addressed through future research.
One of them is the course of infection in patients with obesity. The patients with obesity are well-known to have a low-grade inflammatory state, but it is not yet known how it affects the immune response against the virus. For example, in influenza A viruses, which include the H1N1 virus responsible for the 2009 pandemic, it was shown that important changes occur in the innate and adaptive immune systems, as well as longer viral shedding, both in humans with obesity and in animal models. 170 Another important indicator that should be addressed is how metabolically healthy patients with obesity deal with the disease as compared to metabolically unhealthy patients with obesity from an immune perspective, considering these patients have different inflammatory profiles. 171 Attention should also be paid to the definition of the sample, as there is a continuum ranging from patients without any metabolic compromise to those presenting all symptoms of the metabolic syndrome. 172 The phenotypic characterization of cell populations may also be highly relevant to understanding how obesity affects and is affected by COVID-19 infection. In addition to the cell count, obesity in both young and adult populations is associated with changes in the expression of cytokines, signaling the presence of molecules and receptors in the peripheral blood and adipose tissue. 111,132,133,173 A broader characterization in the blood, adipose tissue, and airways could highlight several aspects of the disease in patients with obesity. Moreover, adipokines may be key players in the disease in the context of patients with obesity. Leptin has been explored in some studies, but there are other hormones, such as adiponectin, resistin, and visfatin, that are also highly relevant due to their metabolic and immune influences. Adipose tissue, specifically, may be a key tissue for immune regulation of the disease in both normal weight and obesity, given the increased ACE-2 expression due to a high-fat diet in this tissue and the role of adipocytes as producers of inflammatory molecules and antigen-presenting cells. 174,175 As one of the key elements in the immune response elicited by vaccines, the antibody response was shown to be more persistent in patients with obesity. 82 Cellular immunity in obesity, however, is not known despite its highly important function following vaccine administration. Although one report suggests a positive correlation between CD4 + central memory cells and BMI in aged patients, 36 it would be interesting to know whether memory B and T cells are effectively generated following the infection and, especially, after vaccination in patients with obesity. The effects of vaccination in the population with obesity also call for additional clarification. Although vaccines are highly effective and safe for this population, the studies included in this scoping review suggest a slightly discrepant post-vaccination immune response in obesity. Longitudinal data on cellular and serologic variables would provide a better picture of this relationship.
In addition to vaccines, the efficacy of pharmacological treatments for COVID-19 in the population with obesity warrants additional research. In this regard, the results for tocilizumab and colchicine have been promising. Both drugs have proven to be effective in reducing inflammation through various pathways: they reduced CRP levels in patients with obesity, while colchicine was also effective in reducing IL-6, IL-16, resistin, complement proteins C5a and C9, and the activity of the COX-2 enzyme. 40,47

| CONCLUDING REMARKS
More than six million people have died worldwide from COVID-19, with many of these deaths in patients with comorbidities, such as obesity. Obesity is a major risk factor for disease severity and death and is associated with a low-grade inflammatory state, which affects the entire body and all the immune branches. In the context of COVID-19 immune response, obesity is associated with several differences as compared to normal-weight individuals that signify a higher inflammatory background in the former (Figures 2 and 3).
Despite the extensive timeline comprising studies made over the last 2 years, there are a number of considerations that have yet to be addressed relative to the COVID-19 pandemic. It remains unclear whether these differences are due to discrepancies in the care received or to molecular mechanisms that predispose certain individuals to develop long-lasting symptoms. The impact of the novel strains on the development of long COVID-19 and which patients will be most affected by them will also require further study. It is not yet known whether this is more prevalent in individuals with obesity and whether the inflammatory state is involved. The exact mechanism also remains unknown.